There is a great need in biomedical applications, including orthopedic practice, for sealants or adhesives of wounds and surgical cuts. Such sealants contemplated could range from sealants used for wound healing and wound closure on the skin to sealants used to permanently seal scalpel cuts and puncture wounds made by large bore injection needles in the course of various procedures.
At present, there is no satisfactory orthopedic sealant being used to satisfy the need for closing iatrogenic defects made in the annulus fibrosa during discectomies. This can cause serious problems in that the intervertebral disc may subsequently undergo accelerated degeneration, and the patient may require a spinal fusion some years later. Some implants have been proposed to resolve the issue but these were introduced without biomechanical considerations. Mechanical barriers have been recently proposed but are fundamentally different from an annulus sealant in that it (1) lacks the ability to reconstruct the annulus directly and restore motion, (2) cannot prevent the leakage of smaller particles from within the nucleus pulposus, (3) is more technically difficult to employ, and (4) would carry a significant risk of neurologic injury if extruded into the canal. No long term data is available on these products.
Further, there is also an unmet need for more flexible wound closure adhesives on the surface of the skin. Currently known wound closure adhesives include 2-octyl-cyanoacrylate (Oct-CA), known commercially by the brand name Dermabond®, available from Ethicon US LLC, a Johnson & Johnson company, wherein Dermabond® is a registered trademark of Johnson & Johnson Company, New Brunswick, N.J., and N-butyl-2-cyanoacrylate, known commercially by either Indermil® tissue adhesive, available from Covidien Co., a Henkel company, wherein Indermil® is a registered trademark of Henkel Corporation, Rocky Hill, Conn., or Histoacryl® topical skin adhesive, available from B. Braun Corporation, wherein Histoacryl® is a registered trademark of Aesculap, Inc., Center Valley, Pa. That is, it is well known that these monomers readily polymerize upon exposure to traces of moisture on surfaces such as skin. The CA group in these compounds is highly reactive toward nucleophiles because of the presence of the two highly electron withdrawing substituents (CN— and COO—), so that CA polymerizations are initiated by moisture. For instance, lower alkyl CAs such as methyl cyanoacrylates or ethyl cyanoacrylate (Superglue®) instantaneously polymerize in the presence of surface moisture. The rates of polymerizations are notably lower with the higher alkyl CAs (e.g., Oct-CA) due to the lower molar concentration of the CA groups.
Accordingly, attempts have been made to increase the rate of polymerization of these higher alkyl CAs (e.g., Oct-CA) without introducing any lower alkyl CAs, since the lower alkyl CAs are known to have toxicity concerns and cannot be used inside the body, but yet provide increase flexibility upon polymerization and higher viscosity than is normally available using commercially available wound closures containing 2-octyl-cyanoacrylate (Oct-CA) as the active ingredient. That is, commercial products such as Dermabond® are known to exhibit undesirably low viscosity (i.e., too runny) and to exhibit undesirable stiffness upon production (i.e., the coatings produced are too stiff and have low tensile strength).
More recently, and to overcome at least the stiffness problem, homopolymer networks containing cyanoacrylate-functionalized multi-arm polyisobutylene stars have been employed to provide more flexibility and rubberyness. These homopolymer networks have been developed and patented. The production of such polyisobutylenes provide for a core (Ø) with a desired number of polyisobutylene arms extending therefrom.
There are many potential biomedical applications with polyisobutylene with attachment of various polymers at the end of each arm. One clinical example where polyisobutylene has been adopted is poly(styrene-b-isobutylene-b-styrene), which is currently used as a coating in the Taxus® Drug Eluting Stent. Another potential application is for all applications where 2-octyl cyanoacrylate (Dermabond®) is currently employed and more flexibility is required.
To that end, cyanoacrylate-telechelic three-arm star polyisobutylenes have been prepared. Cyanoacrylate-telechelic three-arm star polyisobutylenes, Ø(PIB-CA)3, were first prepared in 1991. A low viscosity syringible and injectable homopolymer functionalized with ethyl cyanoacrylate (i.e., Et-CA) was subsequently developed in 2007. It was found that a bolus of covalently linked PIB rubber “superglue” was created when Ø(PIB-CA)3 was injected into (egg) protein and the properties could be controlled by addition of polyethyl-2-cyanoacrylate. On its own, Ø(PIB-CA)3 homonetwork has a tensile strength of 1.6 MPa, Young's Modulus of 4.9 MPa, and an elongation of 70%. Comparatively, the tensile strength of clinically available 2-octyl cyanoacrylate based “superglue”, Dermabond® (Ethicon, J&J) and SurgiSeal™ (Adhezion Biomedical), is less than 0.1 MPa.
Furthermore, it was found that cyanoacrylate-ended tri-telechelic polyisobutylene Ø(PIB-CA)3 (Mn˜2500 g/mol or more) are nontoxic in rats in vivo. Without being bound by theory, it is believed that the biocompatible high barrier rubbery PIB moiety effectively envelops and shields the noxious cyanoacrylate groups from the surrounding tissue and the permanently sequestered -CA groups are rendered harmless. However, too high molecular weight Ø(PIB-CA)3 could also render the benefit of the -CA groups useless as well, as the rate of polymerization would be greatly slowed.
As noted above, it took several years for the production of a co-network of Ø(PIB-CA)3 and Et-CA. This is because Et-CA is not miscible with Ø(PIB-CA)3. It was only by way of mechanical means (i.e., a dual injectable syringe) that the two components could be brought into contact with each other at a particular site for use. Moreover, the amount and molecular weight of Et-CA was such that only small units of 1 to 6 Et-CA units could be used. Accordingly, the result was the production of the mixture of a homonetwork of Ø(PIB-CA)3 and Et-CA homopolymer. That is, the molar ratio of the Ø(PIB-CA)3 to Et-CA was so high that the resultant product is today considered a network, wherein the Et-CA could be thought of as a crosslinker, rather than a polymer portion of a co-network of Ø(PIB-CA)3 and Et-CA. Thus, other alternative networks to Ø(PIB-CA)3 and Et-CA were sought.
Even more recently, new co-networks consisting of relatively low molecular weight Ø(PIB-CA)3 (Mn=1,000-4,000 g/mole) and 2-octyl cyanoacrylate (Oct-CA) have been developed. These low molecular weight Ø(PIB-CA)3 and Oct-CA are miscible liquids and when reacted with a weak nucleophile (as an initiator) will form a co-network. It has been found, however, that these polymer co-networks lack the mechanical properties desirable in a number of biomedical applications. Polymer co-networks formed from higher molecular weight Ø(PIB-CA)3 (Mn>6,000 g/mole) and Oct-CA, on the other hand, have been found to have excellent mechanical properties but, because High-Ø(PIB-CA)3 and Oct-CA, are not fully miscible, a solvent for both High-Ø(PIB-CA)3 and Oct-CA, such as tetrahydrofuran (THF), must be used to permit miscibility. These solvents, however, are generally toxic and cannot be used in many medical and biological applications.
Accordingly, the need exists in the art for other co-networks formed by polymerizing tri-telechelic cyanoacrylate-functionalized polyisobutylene (Ø(PIB-CA)3) and 2-octyl cyanoacrylate (Oct-CA) that have the desired mechanical characteristics, yet do not contain, or otherwise require for use, toxic solvents.